Drugs for chronic pain

ABSTRACT

The present invention relates to nitrooxyderivatives or salts thereof having the following general formula (I): 
 
R—NR 1c —(K) k0 —(B) b0 —(C) c0 —NO 2   (I) 
wherein c0, b0 and k0 are 0 or 1; R is the radical of an analgesic drug for chronic pain, for instance neurophatic pain; 
     R 1c  is H or alkyl with from 1 to 5 carbon atoms; B is such that its precursor is selected from amino acids, hydroxy acids, polyalcohol, compounds; C is a bivalent radical containing an aliphatic, heterocyclic or aromatic radical.

The present invention relates to compounds having an improvedeffectiveness in reducing the chronic pain, specifically the neurophaticpain. In order to describe chronic pain, for simplicity always referenceto neuropathic pain will be made.

It is known that neurophatic pain is a form of chronic pain arising froma damage or disease of the central or peripheral nervous system.Neurophatic pain comprises a series of painful symptomatologies such asdiabetic neurophatic pain, painful post-infarct syndrome, pain caused bychemotherapeutic treatment or pain arising from infections by viralagents, for example herpes, for instance Herpes zoster, etc.

Neurophatic pain generally affects patients for many years, and is asocial problem in that symptoms chronicity induces in subjects seriouspsychological stress.

In last twenty years, research on neurophatic pain pathogenesis hasachieved notable advances. Studies carried out on human and animalexperimental models of neurophatic pain have shown that central nervoussystem reacts to algogen stimuli with a series of biochemical andphysiopathologic responses. This ability of the central nervous systemto functionally and morphologically adapt to algogen stimuli is known asneuroplasticity and plays an essential role in inducing onset or inmaintaining the painful symptomatology.

The usual analgesic drugs actually employed for treating chronic painare partially or absolutely not effective.

Carbamazepine, that has been widely used in clinical studies, h as shownto be active in treating trigeminal neuralgia, diabetic neurophaticpain, and post-herpetic neuralgia. The administration of this drug hasthe drawback to present side effects such as somnolence, dizziness,ataxy, nausea and vomiting, thus limiting its use.

In last years, further drugs for the treatment of neuropathic pain havebeen tested. Among these in particular gabapentin can be mentioned, thatis very active as analgesic drug for treating neurophatic pain, mainlyagainst diabetic neurophatic pain and post-herpetic pain. However, alsoin this case serious adverse effects have been observed, for examplesomnolence, weariness, obesity, etc. (Martindale XXXth Ed, page 374).

It was thus object of the present invention to provide drugs having animproved pharmacotherapeutic profile and/or lower side effects in thetreatment of chronic pain, in particular neurophatic pain.

It has been now surprisingly and unexpectedly found from the Applicantthat this problem can be solved with the class of drugs described below.

The present invention relates to nitrooxyderivatives or salts thereofhaving the following general formula (I):R—NR_(1c)—K)_(k0)—(B)_(b0)—(C)_(c0)—NO₂  (I)wherein

-   c0 is 0 or 1, preferably 1;-   b0 is 0 or 1, with the proviso that c0 and b0 can not be    simultaneously 0;-   k0 is 0 or 1;-   R is the radical of an analgesic drug for chronic pain, for instance    neurophatic pain;-   R_(1c) being H or straight or branched alkyl with from 1 to 5 carbon    atoms;-   K is (CO) or the bivalent radical (1C) having the following formula:    wherein the carbonyl group is bound to T₁; R_(t) and R′_(t), same or    different, are H, C₁-C₁₀-alkyl, phenyl or benzyl, —COOR_(y), in    which R_(y)=H, C₁-C₁₀-alkyl, phenyl, benzyl; B=-T_(B)—X₂-T_(BI)—    wherein    T_(B)=(CO) or X, in which X=O, S, NH;    with the proviso that:    when b0=1 and k0=0, then T_(B)=(CO);    when b0=1 and k0=1, being K=(CO), then T_(B)=X as defined above;    T_(BI)=(CO) or (X), wherein X is as defined above;    when c0=0, then T_(BI)=—O—;    X₂ is such a bivalent bridging group such as the corresponding    precursor of B, having the formula Z-T_(B)-X₂-T_(BI)-Z′ in which Z,    Z′ are independently H or OH, is selected from the following    compounds:

Aminoacids: L-carnosine (CI), penicillamine (CV), N-acetylpenicillamine(CVI), cysteine (CVII), N-acetylcysteine (CVIII):

Hydroxyacids: gallic acid (DI), ferulic acid (DII), gentisic acid(DIII), caffeic acid (DV), hydro caffeic acid (DVI), p-coumaric acid(DVII), vanillic acid (DVIII), syringic acid (DXI):

aromatic polyalcohols: hydroquinone (EVIII), methoxyhydroquinone (EXI),hydroxyhydroquinone (EXII), conyferyl alcohol (EXXXII),4-hydroxyphenetyl alcohol (EXXXIII), p-coumaric alcohol (EXXXIV):

C=bivalent radical having the formula -T_(c)-Y—whereinT_(c)=(CO) or X being as defined above;with the proviso that when b0=0 and k0=1:

-   -   T_(c)=(CO) when K=(1C),    -   T_(c)=X as defined above when K=(CO);        Y has one of the following meanings:        wherein:        nIX is an integer of from 0 to 5, preferably from 1;        nIIX is an integer of from 1 to 5, preferably from 1; R_(TIX),        R_(TIX′), R_(TIIX), R_(TIIX′), the same or different, are H or        straight or branched C₁-C₄-alkyl; preferably R_(TIX), R_(TIX′),        R_(TIIX), R_(TIIX′) are H;        Y³ is a saturated, unsaturated or aromatic heterocyclic ring        with 5 or 6 atoms, containing one to three heteroatoms,        preferably one or two, said heteroatoms being the same or        different and selected from nitrogen, oxygen or sulphur; or Y        may be:        an alkylenoxy group —R′O— in which R′ is straight or branched        C₁-C₂₀, preferably with from 2 to 6 carbon atoms, or a        cycloalkylene with from 5 to 7 carbon atoms, and wherein in        cycloalkylene ring one or more carbon atoms can be replaced by        heteroatoms and the ring may present side chains of R′ type, R′        being as defined above; or one of the following groups:        wherein nf′ is an integer from 1 to 6, preferably from 1 to 4;        wherein R_(1f)=H, CH₃ and nf′ is an integer from 1 to 6;        preferably from 1 to 4;        wherein n3 is an integer from 0 to 5 and n3′ is an integer from        1 to 3; or        in which n3 and n3′ have the meaning mentioned above.

Radical R in formula (I) is preferably a radical of chronic analgesicdrugs, in particular drugs for neurophatic pain, and it can be selectedfrom the usual products available on the market for said use. Thetricyclic antidepressant and antiepileptic drugs can be mentioned.

R is the radical of an analgesic drug having formula (II):

wherein:W is a carbon or nitrogen atom;m is an integer of from 0 to 2;R₀=H, —(CH₂)_(n)—COOR_(y), R_(y) being as defined above;n is an integer of from 0 to 2;R₁=H; when W=N, R₁ is the electronic doublet on nitrogen atom (freevalence);R₂ is selected from the following groups:

-   -   phenyl, optionally substituted with a halogen atom or with a        group selected from —OCH₃, —CF₃, nitro;    -   mono or dihydroxy-substituted benzyl, preferably        3,4-dihydroxybenzyl;    -   amidino group: H₂N(C═NH)—;    -   a radical of formula (IIA), wherein optionally an ethylenic        unsaturation may be present between the carbon atoms in position        1 and 2, or 3 and 4 or 4 and 5:        wherein:        p, p₁, p₂ are integers, same or different, and are 0 or 1;        p₃ in an integer of from 0 to 10;        R₄ is hydrogen, straight or branched C₁-C₆-alkyl, free valence;        R₅ may have the following meanings:    -   hydrogen,    -   straight or branched C₁-C₆-alkyl,    -   C₃-C₆-cycloalkyl,    -   OR_(A), R_(A) having the following meanings:    -   straight or branched C₁-C₆-alkyl, optionally substituted with        one or more halogen atoms, preferably F,    -   phenyl optionally substituted with a halogen atom or with one of        the following groups: —OCH₃, —CF₃, nitro;        R₆, R_(6A), R₇, R₈, the same or different, are H, methyl or free        valence, with the proviso that when an ethylenic unsaturation is        present between C₁ and C₂ in radical of formula (IIA), R₄ and R₅        are free valences able to form the double bond between C₁ and        C₂; if the unsaturation is between C₃ and C₄, R₆ and R₇ are free        valence able to form the double bond between C₃ and C₄; is the        unsaturation is between C₄ and C₅, R₇ and R₈ are free valence        able to form the double bond between C₄ and C₅;    -   Q is H, OH, OR_(B), R_(B) being benzyl, straight or branched        C₁-C₆-alkyl, optionally substituted with one or more halogen        atoms, preferably F, phenyl optionally substituted with a        halogen atom or with one of the following groups: —OCH₃, —CF₃,        nitro;

or Q may have one of the following meanings:

-   -   straight or branched C₁-C₆-alkyl,    -   C₃-C₆-cycloalkyl,    -   guanidino (H₂NC(═NH)NH—),    -   thioguanidino (H₂NC(═S)NH—);        in formula (II) R₂ with R₁ and with W=C form together a C₄-C₁₀        saturated or unsaturated ring, preferably a C₆ saturated one.

When in formula (II) W=C, m=1 and R₀₌—(CH₂)_(n)—COOR_(y), wherein n=1and R_(y)=H; R₂ and R₁ with W as defined above form the cyclohexanering; the drug precursor of R having the formula R—NH₂ is known asgabapentin;

when in formula (II) W=C, m=0 and R₀ if defined as for gabapentin withn=0; R₁=H; R₂ is the radical of formula (IIA) in which p=p₁=1, p₂=p₃=0,R₄=R₅=R₆=R_(6A)=H, Q=H; the drug precursor of R having the formula R—NH₂is known as norvaline;

when in formula (II) W=C, m=0 and R₀ if defined as for gabapentin withn=0; R₁=H; R₂ is the radical of formula (IIA) in which p=p₁=1, p₂=p₃=0,R₄=R₅=R₆=R_(6A)=H, Q is the guanidino group; the drug precursor of Rhaving the formula R—NH₂ is known as arginine;

when in formula (II) W=C, m=0 and R₀ if defined as for gabapentin withn=0; R₁=H; R₂ is the radical of formula (IIA) in which p=p₁=1, p₂=p₃=0,R₄=R₅=R₆=R_(6A)=H, Q is the thioguanidino group; the drug precursor of Rhaving the formula R—NH₂ is known as thiocitrulline;

when in formula (II) W=C, m=1 and R₀ if defined as for gabapentin withn=1; R₁=H; R₂ is the radical of formula (IIA) in which p=p₁=p₂=p₃=0,R₄=H, R₅=Q=CH₃; the drug precursor of R having the formula R—NH₂ isknown as pregabalin;

when in formula (II) W=C and has (S) configuration, m=1 and R₀ ifdefined as for gabapentin with n=1; R₁=H; R₂ is the radical of formula(IIA) in which p=p₁=p₂=p₃=0, R₄=H, R₅=Q=CH₃; the drug precursor of Rhaving the formula R—NH₂ is known as (S)₃-isobutilGABA;

when in formula (II) W=C and has (S), m=0; R₀=R₁=H; R₂ is the radical offormula (IIA) in which p=p₁=1, p₂=p₃=0, R₄=R₅=R₆=R_(6A)=H, Q is theguanidino group; the drug precursor of R having the formula R—NH₂ isknown as agmatine;

when in formula (II) W=C, m=0; R₀ if defined as for gabapentin with n=2;R₁=H; R₂ is the radical of formula (IIA) in which p=p₁=p₂=p₃=0, R₄ andR₅ are free valences and between C₁ and C₂ there is an ethylenicunsaturation, Q=H; the drug precursor of R having the formula R—NH₂ isknown as vigabatrin;

when in formula (II) W=C, m=0; R₀ if defined as for gabapentin with n=0;R₁=H; R₂ is the 3,4-dihydroxybenzyl radical; the drug precursor of Rhaving the formula R—NH₂ is known as2-amino-3-(3,4-dihydroxyphenylpropanoic acid (dopa).

Further compounds employed for chronic pain and that can be used asprecursors of R in formula (I) are lamotrigine, topiramate, zonisamide,carbamazepine, felbamate, amineptine, amoxapine, demexiptiline,desipramine, nortriptyline, tianeptine.

Generally, the drug precursors of R are synthesized according to theprocedures described in “The Merck Index, 12^(th) Ed.” (1996). When thedrug precursors of R present in the molecule the radical of formula(IIA), they can be obtained as described in WO 00/79658.

The precursor compounds of B falling within the groups mentioned abovecan be synthesized according to methods well known in literature andmentioned for example in “The Merck Index, 12^(th) Ed.”, hereincorporated in full for reference.

In formula (III), Y³ is selected from the following bivalent radicals:

Preferred among the Y³ meanings are the following: (Y12), having boththe free valences in ortho position as to the nitrogen atom; (Y16) withboth the valences attached to the heteroatoms,Y1(pyrazole)3,5-disubstituted.

The Y precursors as defined by formula (III), in which the oxygen freevalence is saturated with H and the endstanding carbon atom free valenceis saturated with a carboxylic or hydroxylic group, are productsavailable on the market or they can be obtained according to well knownprocedures.

In formula (I), the B precursors preferred for synthesizing thenitrooxyderivatives to be employed in the present invention are thefollowing: ferulic acid and N-acetylcysteine, the preferred drugprecursors being gabapentin, norvaline, arginine, pregabalin,(S)-3-isobutylGABA, agmatine and vigabatrin.

The preferred compounds of formula (I) of the present invention are thefollowing:

-   1-[4-(nitrooxymethyl)benzoylaminomethyl]-cyclohexaneacetic acid    (XVA),-   1-[3-(nitrooxymethyl)benzoylaminomethyl]-cyclohexaneacetic acid    (XVIA),-   1-[2-(nitrooxymethyl)benzoylaminomethyl]-cyclohexaneacetic acid    (XVIIA),-   1-(4-nitrooxybutanoylaminomethyl)-cyclohexaneacetic acid (XVIIIA),-   1-(nitrooxymethoxycarbonylaminomethyl)-cyclohexaneacetic acid    (XIXA),-   1-{[4-(nitrooxymethyl)benzoyloxy]methoxycarbonylaminomethyl}-cyclohexaneacetic    acid (XXA),-   1-{[3-(nitrooxymethyl)benzoyloxy]methoxycarbonylaminomethyl}-cyclohexaneacetic    acid (XXIA),-   1-{[2-(nitrooxymethyl)benzoyloxy]methoxycarbonylaminomethyl}-cyclohexaneacetic    acid (XXIIA),-   1-[3-(nitrooxymethyl)phenoxycarbonylaminomethyl]-cyclohexaneacetic    acid (XXIIIA),-   {2-methoxy-4-[(1E)-3-[4-(nitrooxybutoxy)-3-oxa-1-propenylphenoxy]-carbonylamino-methyl}-cyclohexaneacetic    acid (XXIVA),-   3-(S)-[4-(nitrooxymethyl)benzoylaminomethyl]-5-methyl-hexanoic acid    (XXVA),-   3-(S)-[3-(nitrooxymethyl)benzoylaminomethyl]-5-methyl-hexanoic acid    (XXVIA),-   3(S)-[2-(nitrooxymethyl)benzoylaminomethyl]-5-methyl-hexanoic acid    (XXVIIA),

3(S)-[4-(nitrooxybutanoyl)aminomethyl]-5-methyl-hexanoic acid (XXVIIIA),

-   3 (S)-[4-(nitrooxymethoxycarbonyl)aminomethyl]-5-methyl-hexanoic    acid (XXIXA),-   3(S)-{[2-(nitrooxymethyl)benzoyloxy]methoxycarbonylaminomethyl}-5-methyl-hexanoic    acid (XXXA),-   3(S)-{[3-(nitrooxymethyl)benzoyloxy]methoxycarbonylaminomethyl}-5-methyl-hexanoic    acid (XXXIA),-   3(S)-[4-(nitrooxymethyl)benzoyloxy]methoxycarbonylaminomethyl}-5-methyl-hexanoic    acid (XXXIIA),-   3(S)-[(3-nitrooxymethyl)phenoxycarbonylaminomethyl]-5-methyl-hexanoic    acid (XXXIIIA),-   3(S)-{2-methoxy-4-[(1E)-3-[4-(nitrooxybutoxy]-3-oxa-1-propenylphenoxy]carbonyl-aminomethyl}-5-methyl-hexanoic    acid (XXXIVA),-   1-[4-(nitrooxybutyloxycarbonyl)aminomethyl]-cyclohexaneacetic acid    (XXXVA),

The compounds of the invention can be used also in form of thecorresponding salts with pharmacologically acceptable cations, such asthe salts of alkali metals.

Having a salifiable nitrogen atom within their molecule, for examplewhen in formula (I) c0=1 and Y=moiety of formula (III), the compounds ofthe present invention can be transformed into the corresponding salts byreaction in an organic solvent, such as acetonitrile, tetrahydrofuran,with an equimolar amount of a corresponding organic or inorganic acid.Examples of organic acid are oxalic, tartaric, maleic, succinic andcitric acids. Examples of inorganic acids are nitric, hydrochloricsulphuric and phosphoric acids. Preferred are the nitrate salts.

The compounds of the invention have shown to possess an improvedactivity for treatment of the chronic pain, in particular neurophaticpain, both as central and peripheric nervous system is concerned.Moreover, it has been surprisingly found that the compounds of theinvention have an improved effect not only reducing neurophatic pain,but also showing unexpectedly a check on pathologic condition progressinducing neurophatic pain. When for example the drugs of the presentinvention are administered to diabetic subjects for diabetic neurophaticpain therapy, it has been found that said compound are able not only toreduce neurophaties, but also to lower diabetes induced complications,for example on blood vessels and/or renal apparatus.

The compounds of the present invention are in particular effective intreating neurophatic pain, for example diabetic naurophatic pain andpost-infarct pain.

The compounds of the invention can be also employed in combination or inadmixture with well known NO-donors. Said compounds contain for exampleone or more ONO₂ or ONO groups within their molecule.

NO-donors that may be used in association with the invention compoundsshould meet the in vitro test described here below. This text relatesthe generation of nitric oxide by NO-donors when in presence ofendothelial cells (method a) or platelets (method b), for examplenitro-glycerine, nicorandil, nitroprussiate, etc.

a) Endothelial Cells

Plated human umbilical vein cells with density of 10³ cells/well, havebeen incubated 5 minutes with NO-donor scalar concentrations (1-100μg/ml). Incubation medium (physiological solvent, i.e. Tyrode) has beenthen analysed to ascertain the ability to generate NO by means of:

1) nitric oxide detection by chemiluminescence,

2) cGMP determination (cyclic GMP No. 2715 of Merck Index mentionedabove).

As far as chemiluminescence analysis is concerned, a 100 μl aliquot hasbeen injected into reaction chamber of an chemiluminescence analyzercontaining glacial acetic acid and potassium iodide. Thenitrites/nitrates present in medium in said conditions are converted inNO which is then revealed owing to its reaction with ozone, withconsequent light production. As usual in devices measuringchemiluminescence, the produced luminescence is directly proportional tothe generated NO levels and can be measured by means of the suitablephotomultiplier unity of an chemiluminescence analyzer. Thephotomultiplier turns incident light into electric voltage, that then isquantitatively registered. Referring to a calibration curve, obtainedwith scalar nitrite concentrations, it has been possible toquantitatively evaluate the concentration of the generated NO. Forexample, from incubation of 100 μl nicorandil, an amount of about 10 μMNO was generated.

In order to determine cGMP, an amount of incubation medium (100 μl) wascentrifuged 20 s at 1 000 rpm. Surnatant was discarded and the sedimentwas treated with frozen phosphate buffer (pH 7.4). The cGMP producedlevels were evaluated by immunoenzyme assay with specific reagents. Fromthese experiments it results that in said experimental conditions theincubation with one of the several tested NO-donors caused a notablecGMP increase in comparison with the values obtained in absence of aNO-donor. For example, after incubation with 100 μM sodiumnitroprussiate a 20 fold increase was registered in comparison with thecorresponding value obtained incubating the vehicle alone withoutNO-donor.

b) Platelets

Washed human platlets have been used, obtained as described by Radomskiet al., (Br. J. Pharmacol. 92, 639-1987). Amounts of 0.4 ml wereincubated 5 minutes with scalar NO-donor concentrations (1-100 μg/ml).The incubation medium (i.e. Tyrode) was then analysed in order todetermine the ability to generate NO by revealing nitric oxide withchemiluminescence technique and cGMP determination using the procedurepreviously described for the analysis carried out on endothelial cells.As to the chemiluminescence assay, also in this case on the basis of acalibration curve plotted with nitrite scalar concentrations, it hasbeen possible to quantitatively define the concentration of thegenerated NO. For example, after incubation of 100 μM nicorandil, anamount of 35 μM of NO was generated.

For determining cGMP, also in these experimental conditions it resultedthat the incubation with one of the several tested NO-donors caused anotable cGMP increase in comparison with the values obtained in absenceof a NO-donor. For example, after incubation with 100 μM sodiumnitroprussiate a 30 fold increase was registered in comparison with thevalue obtained incubating the vehicle alone without NO-donor.

The preferred NO-donors are those containing within the moleculeradicals of the following drugs: aspirin, salicylic acid, ibuprofen,paracetamol, naproxen, diclofenac, flurbiprofen. These preferredcompounds are synthesized as described in patent applications WO95/20641, WO 97/16405, WO 95/09831, WO 01/12584.

The compounds of the invention can be obtained according to thesynthesis procedures described here below.

Generally, should in the drug molecule several reactive groups bepresent, such as COOH and/or HX, wherein X is O, S or NH, they can beprotected before the reaction according to the procedures known fromliterature, for example as described by Th. W. Greene in “ProtectiveGroups In Organic Synthesis”, Harvard University Press, 1980. However,protection of these groups is not strictly necessary for obtaining thecompounds of the present invention.

For preparing the compounds of the present invention, when k0=0 theanalgesic drug amine function was reacted with a reactive compound oflinker C precursor, if b0=0, or of linker B precursor when b0=1.

When in formula (I) b0=0, the analgesic drug was generally reacted withone of the following compounds:

1. if k0=0 and the binding function with the analgesic drug is an amidefunction, the compound reacting with the drug was obtained as follows.

Starting compounds are acyl halides of formula Hal-Y₁—CO-Hal, wherein Y₁is Y as defined above but without the oxygen atom binding NO₂ andHal=Cl, Br, I. These compounds, when not available on the market, may beobtained according to a process well known in the art, for example fromcorresponding acids with thionyl or oxalyl chloride, P^(III) or P^(IV)halides, in solvents inert at the reaction conditions such as toluene,chloroform, DMF etc.

The acyl halide having the formula reported above, was reacted with acarboxylic group condensing agent, such as N-hydroxysuccinimide(SIMD-N—OH) according to methods known from the art, for example inhalogenated solvents in the presence of a base at room temperature,obtaining N-hydroxysuccinimide ester as illustrated in the followingreaction scheme:SIMD-N—OH+Hal-Y₁—CO-Hal---------→SIMD-N—O—CO—Y₁-Hal1a. The hydroxysuccinimide ester was reacted with the amine function ofthe analgesic drug at room temperature in alcoholic and/or chlorinatedsolvents, in presence of an organic or inorganic base according to thefollowing scheme:SIMD-N—O—CO—Y₁-Hal+RNR_(1c)H----------→R—NR_(1c)—CO—Y₁-Hal (2A)1-1. Alternatively, instead of employing the above mentioned acylhalides, hydroxy acids can be used having the formula HO—Y₁—COOH,wherein Y₁ is as defined above, that were reacted withN-hydroxysuccinimide in presence of an agent activating the carboxylicgroup, such as DCC, in halogenated solvents at room temperatureaccording to the following scheme:SIMD-N—OH+HO—Y₁—COOH-----→SIMD-N—O—CO—Y₁—OH1-1.a The compound obtained in 1-1 was reacted with the amine functionof the analgesic drug at the conditions mentioned in _(1a) according tothe following scheme:SIMD-N—O—CO—Y₁—OH+RNR_(1c)H-----→R—NR_(1c)—CO—Y₁—OH (2B)1b. When in formula (I), k0=1 with K=CO, the bond function with theanalgesic drug is a carbamic function. Drug RNR_(1c)H was reacted withan halogenformiate of formula Hal-Y₁—OCO-Hal, wherein Y₁ is as definedabove.

Generally, the employed halogenformiate is available on the market or itcan be obtained from the corresponding alcohols by reaction withtriphosgene in presence of an organic base according to methods wellknown form the art. The reaction of halogenformiate with drug is carriedout in a solvent mixture at room temperature and in presence of a base,for example in water and dioxane or methylene chloride and DMF. Thereaction scheme is the following:Hal-Y₁—OCO-Hal+RNR_(1c)H------→R—NR_(1c)—CO—O—Y₁-Hal (2C)1c. Preparation of nitrooxyderivatives from amides and carbamatesobtained with the procedures mentioned above (b0=0)

When compounds obtained with the reaction described above have theformula R—NR_(1c)—CO—Y₁-Hal (2A) or R—NR_(1c)—CO—O—Y₁-Hal (2C), thecorresponding nitrooxyderivatives have been prepared reacting (2A) or(2C) with AgNO₃ in an organic solvent such as acetonitrile,tetrahydrofuran, at a temperature of from 20° to 100° C. according tothe scheme:R—NR_(1c)—CO—Y₁-Hal (2A)+AgNO₃----→R—NR_(1c)—CO—Y₁—NO₂R—NR_(1c)—CO—O—Y₁-Hal (2C)+AgNO₃----→R—NR_(1c)—CO—O—Y₁—NO₂

When compounds obtained with the reactions described above have theformula R—NR_(1c)—CO—Y₁—OH (2B), the hydroxyl group was subjected tohalogenation, for example with PBr₃, PCl₅, SOCl₂, PPh₃+I₂ at roomtemperature, then it was reacted with AgNO₃ in an organic solvent, suchas acetonitrile, tetrahydrofuran at the conditions mentioned above.Nitrooxyderivatives having the formula R—NR_(1c)—CO—Y₁—NO₂ wereobtained.

1d. When in formula (I), b0=0, k0=1 and for example K=(1C), thefollowing steps were performed. The amine function of the drug wasreacted with the commercially available chloromethyl chloroformiateClC(O)OCH₂Cl. The compound R—NR_(1c)—(CO)—OCH₂Cl thus obtained wasredacted with HO—Y₁—COOH in basic medium as indicated in 1a to give acompound of formula R—NR_(1c)—K—(CO)—Y₁—OH, that was then reacted asabove in 1c to give the corresponding nitrooxyderivative.

2. When in formula (I), b0=c0=1, the synthesis to give the correspondingnitrooxyderivatives involves three steps. In first step, amides (informula (I) k0=0) having substituents containing Hal groups (Hal=Cl, Br,I) or carbamates (in formula (I) k0=1) having substituents containingHal groups as specified below were obtained.

2a. For preparing halogen-substituted amides, the amine function of thedrug was reacted with a N-hydroxysuccinimide ester obtained from an acylhalide of formula P—X₂—COHal, wherein:

-   -   X₂ and Hal are as defined above,    -   P=HX in which X is as defined above or a carboxylic group        protected for example with the corresponding tert-butyl ester,        with N-hydroxysuccinimide (SIMD-N—OH) according to methods known        in the art, for example at room temperature in halogenated        solvents, in presence of a base, to give the compound of formula        R—NR_(1c)—CO—X₂—P that, when P=HX, was reacted with a compound        of formula Hal-Y₁—CO-Hal wherein Hal and Y₁ are as defined        above. The reaction scheme is reported here below:        SIMD-N—OH+P—X₂—COHal----→SIMD-N—O—CO—X₂—P        SIMD-N—O—CO—X₂—P+RNR_(1c)H----→R—NR_(1c)—CO—X₂—P (3A)        R—NR_(1c)—CO—X₂—XH+Hal-Y₁—COHal----→R—NR_(1c)—CO—X₂—X—CO—Y₁-Hal        (3A′)

When in formula (3A) P=ester group as defined above, the carboxylicfunction can be restored with known procedures, for example reactingwith anhydrous HCl in ethyl acetate or dioxane if the starting ester istert-butyl ester. The acid thus obtained was reacted with a halogenatedalcohol of formula Hal-Y₁—OH. The halogenated alcohol are available onthe market.

2a.1 Alternatively, the drug RNR_(1c)H was reacted with aN-hydroxysuccinimide ester, obtained from an acid of formula P—X₂—COOH,wherein P and X₂ are defined above, and N-hydroxysuccinimide(SIMD-N—OH), in presence of dicyclohexylcarbodiimide or anothercondensing agent according to methods well known in the art, for exampleat room temperature in halogenated solvents to give compoundR—NR_(1c)—CO—X₂—P (3A) as for the following scheme:SIMD-N—OH+P—X₂—COOH----→SIMD-N—O—CO—X₂—PSIMD-N—O—CO—X₂—P+RNR_(1c)H----→—NR_(1c)—CO—X₂—P (3A)Compound of formula (3A) was then reacted as described in 2a to give(3A′).2b. Preparation of halogen-substituted carbamates

From compound Hal-Y₁—O—CO—X₂—XH (4A) and triphosgene in presence of anorganic base a halogenformiate of formula Hal-Y₁—O—CO—X₂—XCO-Hal wasprepared according to the scheme reported in 1b. Compound (4A) wasobtained reacting an alcohol of formula Hal-Y₁—OH with HX—X₂—COOH. Thehalogenformiate thus obtained was reacted with the drug amine functionaccording to well known procedures, for example in DMF and/or methylenechloride in presence of a base at room temperature as for the followingscheme:Hal-Y₁—O—CO—X₂—XCO-Hal+RNR_(1c)H----→R—NR_(1c)—CO—X—X₂—COO—Y₁-Hal (3B)2c. Preparation of nitrooxyderivatives from amides and carbamatesobtained in 2a or 2b. Compounds (3A′) or (3B) react in an organicsolvent, such as acetonitrile, tetrahydrofuran, through end standinghalogen with AgNO₃ to give the corresponding nitrooxyderivatives.

Applicant has surprisingly and unexpectedly found that compounds of thepresent invention show a higher activity on chronic pain than thecorresponding precursors.

When compounds of the present invention contain one or more chiralcentres, they can be employed in racemic form, as diastereomer orenantiomer mixture, as pure enantiomers or diastereomers. Should thecompounds have geometric asymmetry, said compounds can be used in cis ortrans form.

The compounds of the present invention are formulated in thecorresponding pharmaceutical compositions for oral, parenteral and topicadministration according to techniques well known in the art with usualexcipients: for example as described in “Remington's PharmaceuticalSciences 15^(th) Ed.”.

The amount on molar basis of the active ingredient in these compositionsis equal or lower then the maximal amount expected for precursor drugs.Due to the excellent tolerability, higher doses can also be employed.The daily doses to be administered are those of the precursor drugs oreventually lower. Said daily doses can be found for example in“Physician's Desk Reference”.

The following examples are to further illustrate but not limit the scopeof the present invention.

EXAMPLES Example 1 Synthesis of1-[4-(nitrooxymethyl)benzoylaminomethyl]cyclohexaneacetic acid (formulaXVA) A) Synthesis of N-hydroxysuccinimidyl 4-(chloromethyl)benzoate

To a solution of N-hydroxysuccinimide (1.375 g, 11.94 mmol) in methylenechloride (30 ml) triethylamine was added (1.66 ml, 11.94 mmol). To thesolution thus obtained, cooled in a water/ice bath, slowly a solution of4-(chloromethyl)benzoyl chloride (2.26 g, 11.94 mmol) in methylenechloride (20 ml) was added. When the adding was over, the mixture wasallowed to stand overnight at room temperature. The mixture was thendried under vacuum to give 4.84 g of a white solid (mixture of thedesired compound and triethylammonium chloride with quantitative yield)that was employed in the next reaction without further purification.

B) Synthesis of 1-[4-(chloromethyl)benzoylaminomethyl]cyclohexaneaceticacid

To a suspension of 1-(aminomethyl)cyclohexaneacetic acid (gabapentin,2.25 g, 13.13 mmol) in absolute ethanol (100 ml) triethylamine was added(3.66 ml, 26.27 mmol) to give a clear solution. In the solution thusobtained and cooled in a water/ice bath, a solution of the equimolarmixture of triethylammonium chloride and N-hydroxysuccinimidyl4-(chloromethyl)benzoate (4.84 g, 11.94 mmol) in methylene chloride (100ml) obtained in A) was dropped. After stirring about 4 hours at roomtemperature, to the mixture ethyl acetate was added (100 ml) and thesolution was extracted with a 4% water solution of hydrochloric acid.The organic phase was dried under vacuum to give 3.85 g of the desiredproduct as a white solid.

C) Synthesis of1-[4-(nitrooxymethyl)benzoylaminomethyl]cyclohexaneacetic acid

To a suspension of1-[4-(chloromethyl)benzoylaminomethyl]cyclohexaneacetic acid (4.01 g,12.39 mmol) in acetonitrrile (250 ml) silver nitrate was added (2.11 g,12.39 mmol). The mixture was stirred at 60° C. under vacuum out of lightadding silver nitrate in five aliquots within about 20 hours. Themixture was heated for 24 hours, adding other 5 equivalents of thesilver nitrate further to those already added. The salt thus formed wasfiltered off, to the mixture ethyl acetate (200 ml) and a 2%hydrochloric acid solution were added. The precipitated insoluble saltswere filtered off and the organic phase was dried under vacuum. The rawmaterial thus obtained was purified by silica gel chromatography withn-hexane/ethyl acetate 6/4 (v/v) as eluent. The product thus obtainedwas crystallized from ethyl acetate/n-hexane to give 2.45 g of a whitesolid with m.p=127-128° C.

¹H-NMR (CDCl₃) ppm: 7.86 (2H, d); 7.50 (2H, d); 7.06 (1H, t); 5.49 (2H,s); 3.54 (2H, d); 2.43 (2H, s); 1.53 (10H, m).

Example 2 Synthesis of1-(nitrooxymethoxycarbonylaminomethyl)cyclohexaneacetic acid (formulaXIXA) A) Synthesis of1-(chloromethoxycarbonylaminomethyl)cyclohexaneacetic acid

To a solution of 1-(aminomethyl)cyclohexaneacetic acid (gabapentin, 2.00g, 11.68 mmol) in a water (30 ml) and dioxane (20 ml) mixture,diisopropylethylamine was added (4.06 ml, 23.36 mmol). In the solutionthus obtained, and cooled in a water/ice bath, chloromethylchloroformiate (1.25 ml, 14.02 mmol) dissolved in dioxane (20 ml) wasslowly dropped. At the end of adding, the mixture was allowed to stand 3hours at room temperature. The mixture was then poured in a 4%hydrochloric acid solution to sink the end pH value to about 2. Ethylacetate was added and the organic phase<was dried under vacuum to give2.87 g of a clear, yellow oil that was employed in the next reactionwithout further purification.

B) Synthesis of 1-(nitrooxymethoxycarbonylaminomethyl)cyclohexaneaceticacid

To a solution of 1-(chloromethoxycarbonylaminomethyl)cyclohexaneaceticacid (2.87 g, 10.92 mmol) in acetonitrile (25 ml) silver nitrate wasadded (3.71 g, 21.84 mmol). The mixture was stirred 3 hours under vacuumout of light at 40° C. The precipitated salt was filtered off and to themixture ethyl acetate (30 ml) and a 2% hydrochloric acid solution wereadded. The salts thus formed was removed by filtration and the organicphase was dried under vacuum. The oily product thus obtained waspurified by silica gel chromatography with n-hexane/ethyl acetate 6/4(v/v) as eluent to give 2.68 g of colourless oil,

¹H-NMR (CDCl₃) ppm: 6.03 (2H, s); 5.51 (1H, t); 3.30 (2H d), 2.36 (2H,s); 1.47 (10H, m).

Example 3 Synthesis of1-[3-(nitrooxymethyl)phenoxycarbonylaminomethyl)cyclohexaneacetic acid(formula XXIIIA) A) Synthesis of1-[3-(bromomethyl)phenoxycarbonylaminomethyl)cyclohexaneacetic acid

To a suspension of 3-bromomethylphenol (0.50 g, 2.67 mmol) in methylenechloride (8 ml), bis(trichloromethyl)carbonate (triphosgene, 0.368 g,1.24 mmol) dissolved in methyl chloride (2 ml) and diisopropylethylamine(0.466 ml, 2.67 mmol) were cool added. The solution thus obtained wasstirred one night at room temperature and then refluxed for 2 hours,This cooled solution was then dropped in a suspension of1-(aminomethyl)cyclohexaneacetic acid (gabapentin, 0.911 g, 5.35 mmol)and diisopropylethylamine (0.932 ml, 5.35 mmol) in anhydrousdimethylformamide (4 ml). After 3 hours stirring, to the mixture ethylacetate was added and it was washed with a 4% hydrochloric acidsolution. The organic phase was dried under vacuum and the raw productthus obtained was purified by silica gel chromatography withn-hexane/ethyl acetate 1/1 (v/v) as eluent. The desired product wasobtained as an oil (0.100 g) that was employed without furtherpurification.

B) Synthesis of1-[3-(nitrooxymethyl)phenoxycarbonylaminomethyl)cyclohexane-acetic acid

To a suspension of1-[3-(bromomethyl)phenoxycarbonylaminomethyl)cyclohexaneacetic acid(0.100 g, 0.26 mmol) in acetonitrile (2 ml) silver nitrate was added(0.100 g, 0.59 mmol). The mixture was stirred overnight at roomtemperature under nitrogen atmosphere out of light. The salt thus formedwas filtered off and to the mixture ethyl acetate (5 ml) and a 2%hydrochloric acid solution were added. Insoluble salts were filtered offand the organic phase was purified by silica gel chromatography withmethylene chloride/methanol 97/3 (v/v) as eluent, to give 0.080 g ofproduct as an oil.

¹H-NMR (CDCl₃) ppm: 7.38 (1H, t); 7.22 (3H, m); 5.68 (1H, t); 5.43 (2H,s); 3.34 (2H, d); 2.41 (2H, s); 1.49 (10H, m).

Example 4 Synthesis of1-[4-(nitrooxybutyloxycarbonyl)aminomethyl]cyhclohexaneacetic acid(formula XXXVA) A) Synthesis of1-[4-(chlorobutyloxycarbonyl)aminomethyl]cyclohexaneacetic acid

To a solution of 1-(aminomethyl)cyclohexaneacetic acid (1.95 g, 11.4mmol) in dioxane/water (1:1, 40 ml), N,N-diisopropylethylamine was added(4.00 ml, 23.0 mmol) and the solution was cooled at 0° C. Then1-chlorobutyl chloroformiate was slowly added (1.30 ml, 9.50 mmol) andthe reaction was allowed to reach room temperature and maintained 5hours under stirring. The mixture was diluted with methylene chlorideand washed with 4% aqueous hydrochloric acid, dehydrated and dried undervacuum, to give 2.87 g of an colourless oil that was employed in thenext reaction without further purification.

B) Synthesis of 1-[4-(iodobutyloxycarbonyl)aminomethyl]cyclohexaneaceticacid

To a solution of1-[4-(chlorobutyloxycarbonyl)aminomethyl]cyclohexaneacetic acid (1.68 g,5.70 mmol) in acetonitrile (26 ml), sodium iodide was added (8.48 g,57.0 mmol) and the reaction mixture was refluxed 5 hours under stirring.The solvent was then removed under vacuum and the residue treated withmethylene chloride. The organic phase was washed with water, dehydratedand dried under vacuum to give 2.12 g of an oily product that wasemployed in the next step without purification.

C) Synthesis of1-[4-(nitrooxybutyloxycarbonyl)aminomethyl]cyhclohexaneacetic acid

To a solution of1-[4-(iodobutyloxycarbonyl)aminomethyl]cyclohexaneacetic acid (2.12 g,5.30 mmol) in acetonitrile (25 ml), silver nitrate was added (2.42 g,14.2 mmol). The mixture was stirred 5 hours at 40° C. under nitrogenatmosphere and out of light, then it was filtered on celite andconcentrated. The residue was treated with methylene chloride andextracted with a 4% hydrochloric acid solution. The salts thus formedwere filtered off and the aqueous phase was extracted with methylenechloride. The organic phases were washed with a saturated sodiumchloride solution, dehydrated and dried under vacuum. The oily residuewas dissolved in ethyl ether, filtered on celite and dried under vacuumto give 1.64 g of an oily product.

¹H-NMR (CDCl₃) ppm: 5.65 (1H, m); 4.49 (2H, t); 4.12 (2H, t); 3.23 82H,d); 2.34 (2H, s); 1.9-1.7 (4H, m); 1.6-1.3 (10H, m).

Example F1 Evaluation of Analgesic Activity of the Compounds of theInvention by Writhing Test (Vinegar et al., 1979)

Nine groups of male Swiss mice (20-25 g, Charles River), 10 animalseach, received by oral administration through gastric tube (gavage)gabapentin in an amount of from 1 to 10 mg/kg or the compound of theinvention (XVA, Example 1), hereinafter NO-gabapentin, in an amount offrom 1 to 10 mg/kg dissolved in saline solution. One hour afteradministration of the compound solutions, through intraperitonealinjection the mice received a glacial acetic acid solution (0,5 ml,0.6%). Within 15 minutes subsequent to the administration of aceticacid, in every animal the number of abdominal contractions was counted.Analysis was carried out in blind.

The results reported in Table 1 are given as the number of totalcontractions within the observation time (15 minutes). The results showthat NO-gabapentin is more active than precursor drug in inhibitingabdominal contraction amount.

Example F2 Evaluation of Analgesic Activity of the Compounds of theInvention by Paw Licking Test

Three groups of male Swiss mice (20-25 g, Charles River), 10 animalseach, received by oral administration as in Example F1 gabapentin in anamount of 3 mg/kg (17.5 μm/kg) or the compound of formula (XVA, Example1), hereinafter NO-gabapentin, in an amount of 3 mg/kg (8.5 μm/kg)dissolved in saline solution. The control group received an equal volumeof saline solution. One hour after administration of the compoundsolutions, the mice were injected with formalin in the paw (10 μl).

The formalin injection induced a biphasic reaction. In first phase(phase I, 0-15 minutes) an acute inflammation was observed; in thesecond phase (phase II, 15-30 minutes) a release of chemical mediatorsoccurred as in neurophatic pain. Within 30 minutes subsequent toformalin injection, in each animal the time in seconds in which theanimal licked its paw was recorded. Analysis was carried out in blind.

The results reported in Table 2 are expressed as the entire time inseconds in which paw licking in animals during the first and secondphase as defined above was observed.

The results show that NO-gabapentin is more active than the startingdrug in inhibiting paw licking in first phase even though administeredat a molar dose corresponding to 50% of gabapentin. For this reason, insecond phase NO-gabapentin is less effective.

Example F3 Evaluation of Analgesic Activity of the Compounds of theInvention in Animal Models of Neuropathic Pain

We have tested the antinoceptive effects of compound of formula (XVA,Example 1), hereinafter NO-gabapentin, in the model of neuropathic painconstitued by the chronic constriction injury of the rat sciatic nerve.The parent compound gabapentin has been used as reference drug.

The unilateral peripheal mononeuropathy was obtained according to themethod described by Bennet G J and Xie Y K, Pain (33) 1988: 87-107.Sample populations ranging from 8 to 12 rats (SD males weighting 250-300g) for condition were used. The antinoceptive effect of the drugs wasdetermined by measuring the vocalization threshold (VTPP) elicited bypaw pressure both at the injuried and at the controlateral side. Thetest was performed at day 14 post lesion. All compounds were tested foracute antinoceptive effects. Acute effects were determined within 60 minfollowing a single intraperitoneal (i.p.) injection of the drugs priorto the test.

Each group of the rats received gabapentin at the dose of 30 mg/kg (175μmoles/kg), or an equimolar dose of NO-gabapentin (175 μmoles/kg), orthe same volume of vehicle (Control group). The drugs were dissolved (20mg/mL) in vehicle containing saline: DMSO: Castor oil (68:8:24).

The results are reported in Table 3 and show that NO-gabapentin was moreefficacious than gabapentin. TABLE 1 Evaluation of gabapentin andNO-gabapentin analgesic activity in experiment F1 (writhing test)Treatment Dose (mg/kg) Contractions number Controls — 39 Gabapentin 1 32NO-gabapentin 1 24 Gabapentin 3 22 NO-gabapentin 3 15 Gabapentin 10  27NO-gabapentin 10  15

TABLE 2 Evaluation of gabapentin and NO-gabapentin analgesic activity inexperiment F2 (formalin injected in rats paw) paw licking (sec)Treatment Dose (μm/kg) Phase I Phase II Controls — 125  185  Gabapentin17.5 85 30 NO-gabapentin 8.5 50 60

TABLE 3 Evaluation of gabapentin and NO-gabapentin analgesic activity inexperiment F3 (model of neuropathic pain) Vocalization threshold topressure in the injured paw (VTPP) (grams) Time Post-dosing gabapentinNO-gabapentin (min) Control (175 μmoles/kg, ip) (175 μmoles/kg, ip)  0144 ± 10 160 ± 10 153 ± 10  5 156 ± 10 165 ± 23 187 ± 10 10 162 ± 14 191± 29 307 ± 14 20 150 ± 08 250 ± 24 325 ± 08 40 159 ± 11 266 ± 26 390 ±11 60 150 ± 09 250 ± 38 382 ± 09

1. Nitrooxyderivatives or salts thereof having the following general formula (I) R—NR_(1c)(K)_(k0)—(B)_(b0)—(C)_(b0)—NO₂  (I) wherein c0 is 0 or 1; b0 is 0 or 1, with the proviso that c0 and b0 can not be simultaneously 0; k0 is 0 or 1; R is the radical of an analgesic drug for chronic pain; R_(1c), being H or straight or branched alkyl with from 1 to 5 carbon atoms; K is (CO) or the bivalent radical (1C) having the following formula:

wherein the carbonyl group is bound to T₁; R_(t) and R′_(t), same or different, are H, C₁-C₁₀-alkyl, phenyl or benzyl, —COOR_(y), in which R_(y)=H, C₁-C₁₀-alkyl, phenyl, benzyl; B=-T_(B)-X₂-T_(BI)- wherein T_(B)=(CO) or X, in which X=O, S, NH; with the proviso that: when b0=1 and k0=0, then T_(B)=(CO); when b0=1 and k0=1, being K=(CO), then T_(B)=X as defined above; T_(BI)=(CO) or (X), wherein X is as defined above; when c0=0, then T_(BI)=-0-; X₂ is such a bivalent bridging group such as the corresponding precursor of B, having the formula Z-T_(B)-X₂-T_(BI)-Z′ in which Z, Z′ are independently H or OH, is selected from the following compounds: Aminoacids: L-carnosine (CI), penicillamine (CV), N-acetylpenicillamine (CVI), cysteine (CVII), N-acetylcysteine (CVIII):

Hydroxyacids: gallic acid (DI), ferulic acid (DII), gentisic acid (DIII), caffeic acid (DV), hydro caffeic acid (DVI), p-coumaric acid (DVII), vanillic acid (DVIII), syringic acid (DXI):

aromatic polyalcohols: hydroquinone (EVIII), methoxyhydroquinone (EXI), hydroxyhydroquinone (EXII), conyferyl alcohol (EXXXII), 4-hydroxyphenetyl alcohol (EXXXIII), p-coumaric alcohol (EXXXIV):

C=bivalent radical having the formula -T_(c)-Y wherein T_(c)=(CO) or X being as defined above; with the proviso that when b0=0 and k0=1: -T_(c)=(CO) when K=(1C), -T_(c)=X as defined above when K=(CO); and Y has one of the following meanings:

wherein: nIX is an integer of from 0 to 5; nIIX is an integer of from 1 to 5; R_(TIX), R_(TIX′), R_(TIIX), R_(TIIX′), the same or different, are H or straight or branched C₁-C₄-alkyl; Y³ is a saturated, unsaturated or aromatic heterocyclic ring with 5 or 6 atoms, containing one to three heteroatoms, said heteroatoms being the same or different and selected from nitrogen, oxygen or sulphur; or Y may be: an alkylenoxy group —R′O— in which R′ is straight or branched C₁-C₂₀ or a cycloalkylene with from 5 to 7 carbon atoms, and wherein in cycloalkylene ring one or more carbon atoms can be replaced by heteroatoms and the ring may present side chains of R′ type, R′ being as defined above; or one of the following groups:

wherein nf′ is an integer from 1 to 6;

wherein R_(1f)=H, CH₃ and nf′ is an integer from 1 to 6;

wherein n3 is an integer from 0 to 5 and n3′ is an integer from 1 to 3; or

in which n3 and n3′ have the meaning mentioned above; R is the radical of an analgesic drug having formula (II):

wherein: W is a carbon or nitrogen atom; m is an integer of from 0 to 2; R₀=H, —(CH₂)_(n)—COOR_(y), R_(y) being as defined above; n is an integer of from 0 to 2; R_(I)=H; when W=N, R₁ is the electronic doublet on nitrogen atom (free valence); R₂ is selected from the following groups: phenyl, optionally substituted with a halogen atom or with a group selected from —OCH3, —CF3, nitro; mono or dihydroxy-substituted benzyl, preferably 3,4-dihydroxybenzyl; amidino group: H₂N(C═NH)—; a radical of formula (IIA), wherein optionally an ethylenic unsaturation may be present between the carbon atoms in position 1 and 2, or 3 and 4 or 4 and 5:

wherein: p, p₁, p₂ are integers, same or different, and are 0 or 1; p₃ in an integer of from 0 to 10; R₄ is hydrogen, straight or branched C₁-C₆-alkyl, free valence; R₅ may have the following meanings: hydrogen, straight or branched C₁-C₆-alkyl, C₃-C₆-cycloalkyl, OR_(A), R_(A) having the following meanings: straight or branched C₁-C₆-alkyl, optionally substituted with one or more halogen atoms, preferably F, phenyl optionally substituted with a halogen atom or with one of the following groups: —OCH₃, —CF₃, nitro; R₆, R_(6A), R₇, R₈, the same or different, are H, methyl or free valence, with the proviso that when an ethylenic unsaturation is present between C₁ and C₂ in radical of formula (IIA), R₄ and R₅ are free valences able to form the double bond between C₁ and C₂; if the unsaturation is between C₃ and C₄, R₆ and R₇ are free valence able to form the double bond between C₃ and C₄; is the unsaturation is between C₄ and C₅, R₇ and R₈ are free valence able to form the double bond between C₄ and C₅; Q is H, OH, OR_(B), R_(B) being benzyl, straight or branched C₁-C₆-alkyl, optionally substituted with one or more halogen atoms, preferably F, phenyl optionally substituted with a halogen atom or with one of the following groups: —OCH₃, —CF₃, nitro; or Q may have one of the following meanings: straight or branched C₁-C₆-alkyl, C₃-C₆-cycloalkyl, guanidino (H₂NC(═NH)NH—), thioguanidino (H₂NC(═S)NH—). in formula (II) R₂ with R₁ and with W=C form together a C₄-C₁₀ saturated or unsaturated ring.
 2. Compounds according to claim 1, characterized in that Y³ in formula (III) is selected 25 from:


3. Compounds according to claim 1, characterized in that in formula (I): c0 is I; b0 is 0 or 1; k0 is 0 or 1; R_(1c), ═H; K is (CO) or the bivalent radical (1C) as defined in claim 1; B=-T_(B)-X₂-T_(BI)- wherein T_(B)=(CO) or X, in which X=O, S, NH; with the proviso that: when b0=1 and k0=0, then T_(B)=(CO); when b0=1 and k0=I, being K=(CO), then T_(B)=X as defined above; T_(BI)=(CO) or (X), wherein X is as defined above; when c0=0, then T_(BI)=—O—; the precursor of B is N-acetylcysteine or ferulic acid; C=bivalent radical having the formula -T_(c)-Y— wherein T_(c)=(CO) or X being as defined above; with the proviso that when b0=0 and k0=1: T_(c)=(CO) when K=(1C), T_(c)=X as defined above when K=(CO); and Y has one of the following meanings:

wherein: nIX and nIIX are 1; R_(TIX), R_(TIX′)′, R_(TIIX), R_(TIIX′) are H; Y³ is selected from the following bivalent radicals:

or Y may be: an alkylenoxy group —R′O— in which R′ is straight or branched C₂-C₆ alkyl; or

wherein Rif=H, CH3 and nfl is an integer from 1 to 4;

wherein n3 is an integer from 0 to 3 and n3′ is an integer from 1 to 3; R is the radical of an analgesic drug having formula (II):

wherein: W is a carbon atom; m is 0 or 1; R₀=H or —(CH₂)_(n), COOH, wherein n is an integer of from 0 to 2; R₁H; R₂ is selected from the following groups: 3,4-dihydroxybenzyl; or a radical of formula (IIA) as defined in claim 1, wherein: p and p_(I) are are 0 or 1; p₂ and p₃ are 0; R₄ and R₅ are hydrogen, straight or branched C₁-C₆-alkyl or free valence; R₆ and R_(6A) are H; with the proviso that when an ethylenic unsaturation is present between C₁ and C₂ in radical of formula (IIA), R₄ and R₅ are free valences able to form the double bond between C₁ and C₂; Q is H, CH₃ or guanidino (H₂NC(═NH)NH—), or thioguanidino (H₂NC(═S)NH—); in formula (II) R₂ with R₁ and with W form together a C₆ saturated ring.
 4. Compounds according to claim 1, wherein when in formula (II) W=C, m=1 and R₀=—(CH2)_(n)—COOR_(y), wherein n=1 and R_(y)=H; R₂ and R_(I) with W as defined above form the cyclohexane ring; the drug precursor of R having the formula R—NH₂ is known as gabapentin; when in formula (II) W=C, m=0 and R₀ if defined as for gabapentin with n=0; R_(I)=H; R₂ is the radical of formula (IIA) in which p=p_(I)=1, p₂=p₃=0, R₄=R₅=R₆=R_(6A)=H, Q=H; the drug precursor of R having the formula R—NH₂ is known as norvaline; when in formula (II) W=C, m=0 and R₀ if defined as for gabapentin with n=0; R₁=H; R₂ is the radical of formula (IIA) in which p=p_(I)=I, p₂=p₃=0, R₄=R₅=R₆=R_(6A)=H, Q is the guanidino group; the drug precursor of R having the formula R—NH₂ is known as arginine; when in formula (II) W=C, m=0 and R₀ if defined as for gabapentin with n=0; R_(I)=H; R₂ is the radical of formula (IIA) in which p=p₁=1, p₂=p₃=0, R₄=R₅=R₆=R_(6A)=H, Q is the thioguanidino group; the drug precursor of R having the formula R—NH₂ is known as thiocitrulline; when in formula (II) W=C, m=1 and R₀ if defined as for gabapentin with n=1; R₁=H; R₂ is the radical of formula (IIA) in which p=p₁=p₂=p₃=0, R₄=H, R₅=Q=CH₃; the drug precursor of R having the formula R—NH₂ is known as pregabalin; when in formula (II) W=C and has (S) configuration, m=1 and R₀ if defined as for gabapentin with n=1; R₁=H; R₂ is the radical of formula (IIA) in which p=p₁=p₂=p₃=0, R₄=H, R₅=Q=CH₃; the drug precursor of R having the formula R—NH₂ is known as (S)₃-isobutilGABA; when in formula (II) W=C and has (S), m=0; R₀=R₁=H; R₂ is the radical of formula (IIA) in which p=p₁=1, p₂=p₃=0, R₄=R₅=R₆=R_(6A)=H, Q is the guanidino group; the drug precursor of R having the formula R—NH₂ is known as agmatine; when in formula (II) W=C, m=0; R₀ if defined as for gabapentin with n=2; R₁=H; R₂ is the radical of formula (IIA) in which p=p₁=p₂=p₃=0, R₄ and R₅ are free valences and between C₁ and C₂ there is an ethylenic unsaturation, Q=H; the drug precursor of R having the formula R—NH₂ is known as vigabatrin; when in formula (II) W=C, m=0; R₀ if defined as for gabapentin with n=0; R₁=H; R₂ is the 3,4-dihydroxybenzyl radical; the drug precursor of R having the formula R—NH₂ is known as 2-amino-3-(3,4-dihydroxyphenylpropanoic acid (dopa).
 5. Compounds according to claim 1, wherein the drug precursors of R in formula (I) are selected from lamotrigine, topiramate, zonisamide, carbamazepine, felbamate, amineptine, amoxapine, demexiptiline, desipramine, nortriptyline, tianeptine.
 6. Compounds according to claims 1, selected from: 1-[4-(nitrooxymethyl)benzoylaminomethyl]-cyclohexaneacetic acid (XVA),

1-[3-(nitrooxymethyl)benzoylaminomethyl]-cyclohexaneacetic acid (XVIA),

1-[2-(nitrooxymethyl)benzoylaminomethyl]-cyclohexaneacetic acid (XVIIA),

1-(4-nitrooxybutanoylaminomethyl)-cyclohexaneacetic acid (XVIIIA),

1-(nitrooxymethoxycarbonylaminomethyl)-cyclohexaneacetic acid (XIXA),

1-{[4-(nitrooxymethyl)benzoyloxy]methoxycarbonylaminomethyl}-cyclohexaneacetic acid (XXA),

1-{[3-(nitrooxymethyl)benzoyloxy]methoxycarbonylaminomethyl}-cyclohexaneacetic acid (XXIA),

1-{[2-(nitrooxymethyl)benzoyloxy]methoxycarbonylaminomethyl}-cyclohexaneacetic acid (XXIIA),

1-[3-(nitrooxymethyl)phenoxycarbonylaminomethyl]-cyclohexaneacetic acid (XXIIIA),

{2-methoxy-4-[(1E)-3-[4-(nitrooxybutoxy)-3-oxa-I-propenylphenoxy]-carbonylaminomethyl)-cyclohexaneacetic acid (XXIVA),

3-(S)-[4-(nitrooxymethyl)benzoylaminomethyl]-5-methyl-hexanoic acid (XXVA),

3-(S)-[3-(nitrooxymethyl)benzoylaminomethyl]-5-methyl-hexanoic acid (XXVIA),

3(S)-[2-(nitrooxymethyl)benzoylaminomethyl]-5-methyl-hexanoic acid (XXVIIA),

3(S)-[4-(nitrooxybutanoyl)aminomethyl]-5-methyl-hexanoic acid (XXVIIIA),

3(S)-[4-(nitrooxymethoxycarbonyl)aminomethyl]-5-methyl-hexanoic acid (XXIXA),

3(S)-{[2-(nitrooxymethyl)benzoyloxy]methoxycarbonylaminomethyl}-5-methyl-hexanoic acid (XXXA),

3(S)-{[3-(nitrooxymethyl)benzoyloxy]methoxycarbonylaminomethyl}-5-methylhexanoic acid (XXXIIA),

3(S)-[4-(nitrooxymethyl)benzoyloxy]methoxycarbonylaminomethyl)-5-methylhexanoic acid (XXXIIA),

3(S)-[3-(nitrooxymethyl)phenoxycarbonylaminomethyl]-5-methyl-hexanoic acid (XXXIIIA),

3(S)-{2-methoxy-4-[(1E)-3-[4-(nitrooxybutoxy]-3-oxa-I-propenylphenoxy]carbonylaminomethyl}-5-methyl-hexanoic acid (XXXIVA),

1-[4-(nitrooxybutyloxycarbonyl)aminomethyl]-cyclohexaneacetic acid (XXXVA),


7. Compounds according to claim 1, in combination with NO-donor compounds.
 8. Compounds according to claim 7, wherein the NO-donors contain in the molecule radicals of the following drugs: aspirin, salicylic acid, ibuprofen, paracetamol, naproxen, diclofenac and flurbiprofen.
 9. Pharmaceutical compositions comprising compounds according to claim 1 as active ingredients.
 10. Compounds according to claim 1 to be employed as a drug.
 11. Use of the compounds according to claim 1 for preparing drugs for chronic pain.
 12. Use of the compounds according to claim 11, wherein the chronic pain is neurophatic pain. 